This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rabies virus (RV), a single-stranded RNA virus of the Rhabdovirus family, has been developed as a novel vaccine candidate for HIV-1. As a live-attenuated vaccine in mice, RV has been shown to induce vigorous and long lasting immune responses to both HIV-1 Env and Gag. Further, the single RV glycoprotein (G) can be functionally replaced by HIV-1 Env if the gp160 cytoplasmic tail domain (CD) is replaced by that of RV G. These surrogate, or G-deleted (deltaG), viruses expressing Env assume an HIV-1-like cell tropism and are therefore targeted to CD4+/HIV-1 co-receptor positive cells. Recent research results indicate that even previous promising HIV-1 vaccine approaches, which prevented an AIDS-like disease in rhesus macaques, failed. We hypothesize that successful HIV-1 vaccines need strong humoral and cellular immune responses and our preliminary data indicate that such responses can be induced by RV-based HIV vaccines. This project is directed towards the further detailed analysis of the immunogenicity of RVbased HIV-1 vaccines and the improvement of their immunogenicity. To date we have immunized a total of 12 animals. Four rhesus macaques received RV expressing SIVmac239 Gag and Pol followed by a boost at 8 weeks with a RV-VSVG virus expressing SIVmac239 Gag and Pol. A second group of four animals were immunized with the same schedule and vectors expressing SIVmac239 env in addition to Gag and Pol. A third group of 4 animals was immunized using the same schedule with the same empty vectors (no SIV proteins) as a control. All the animals are challenged with SIVmac251 at 20 weeks post immunization.